Tumor Microenvironment-Responsive Shell/Core Composite Nanoparticles for Enhanced Stability and Antitumor Efficiency Based on a pH-Triggered Charge-Reversal Mechanism.

High systemic stability and effective tumor accumulation of chemotherapeutic agents are indispensable elements that determine their antitumor efficacy. PEGylation of nanoparticles (NPs) could prolong the retention time in vivo by improving their stability in circulation, but treatment suffers reduced tumor penetration and cellular uptake of nanomedicines. The tumor microenvironment (TME)-responsive NPs maintain their stealth features during circulation and undergo a stimuli-responsive dePEGylation once exposed to the site of action, thereby achieving enhanced internalization in tumor cells. Herein, TME-responsive shell/core composite nanoparticles were prepared and optimized with enhanced stability and tumor intake efficiency. We synthesized 12-hydroxystearic acid-poly (ethylene glycol)-YGRKKRRQRRR (HA-PEG-TAT) as a post-insert apparatus in disulfiram (DSF)-encapsulated naked nanoparticles (N-NPs) in order to form a cationic core (TAT-NPs). Accordingly, the negatively charged poly (glutamate acid)-graft-poly (ethylene glycol) (PGlu-PEG) was further applied to the surface of TAT-NPs as a negative charged shell (PGlu-PEG/TAT-NPs) via the electrostatic interaction between glutamic acids and arginine at the outer ring of the TAT-NPs. PGlu-PEG/TAT-NPs displayed a huge loading capability for DSF with reduced degradation in plasma and exhibited rapid charge reversal when pH decreased from 7.4 to pH 6.5, demonstrating an excellent systemic stability as well as intelligent stimuli-responsive performance within the acidic TME. Furthermore, the in vivo antitumor study revealed that PGlu-PEG/TAT-NPs provided greater antitumor efficacy compared with free DSF and N-NPs with no obvious systemic toxicity. In conclusion, the TME-responsive shell/core composite NPs, consisting of PGlu-PEG and HS-PEG-TAT, could mediate an effective and biocompatible delivery of chemotherapeutic agents with clinical potential.